Microtubules are cytoskeletal structures assembled from α/β tubulin heterodimers that play an essential role in many cellular processes, such as cell motility, organelle transport, maintenance of cell polarity and cell division. Interference with microtubule dynamics by stabilization or destabilization in dividing cells leads to cell division arrest in the G2/M phase and cell death.
A variety of clinically promising compounds which demonstrate potent cytotoxicity and antitumor activity are known to effect their primary mode of action through an efficient inhibition of tubulin. Several natural products and their derivatives disrupt microtubule dynamics, e.g., Taxol®, Taxotere®, Navelbine® and show a clinically useful therapeutic window between anticancer effects and dose-limiting toxicity in normal proliferating tissues, notably bone marrow and gastrointestinal mucosa in addition to neurotoxicity. Unfortunately the clinical success of these agents can be severely hindered by the emergence of drug resistant tumor cells. Although membrane P-glycoprotein mediated multi-drug resistance (MDR) has been known to occur with the taxanes and the Vinca alkaloids, differential expression of altered tubulin isotypes has also been implicated in resistance to the taxanes and other antimitotic agents.
Renewed interest in tubulin polymerisation inhibitors has been generated by the hope that non-MDR substrates that interact with tubulin at sites near to, overlapping with or different from those of the taxanes or the Vinca alkaloids can be discovered.
Novel tubulin-binding molecules which, upon binding to tubulin, interfere with tubulin polymerization can provide novel agents for the treatment of proliferative diseases.
Pyrrolobenzimidazolones are known in the state of the art as agents with an antithrombotic and cardiovascular effect. DE3639466A1, DE3642315A1 and DE4027592A1 describe the use of pyrrolobenzimidazolones for the treatment of heart and circulatory diseases.